Immune Regulatory Cell Bias Following Alemtuzumab Treatment in Relapsing-Remitting Multiple Sclerosis.

Alemtuzumab is a highly effective treatment for relapsing-remitting multiple sclerosis. It selectively targets the CD52 antigen to induce profound lymphocyte depletion, followed by recovery of T and B cells with regulatory phenotypes. We previously showed that regulatory T cell function is restored with cellular repletion, but little is known about the functional capacity of regulatory B-cells and peripheral blood monocytes during the repletion phase.

Repopulation of T, B, and NK cells following alemtuzumab treatment in relapsing-remitting multiple sclerosis.

Objective: To characterize long-term repopulation of peripheral immune cells following alemtuzumab-induced lymphopenia in relapsing-remitting MS (RRMS), with a focus on regulatory cell types, and to explore associations with clinical outcome measures.

Methods: The project was designed as a multicenter add-on longitudinal mechanistic study for RRMS patients enrolled in CARE-MS II, CARE-MS II extension at the University of Southern California and Stanford University, and an investigator-initiated study conducted at the Universities of British Columbia and Chicago. Methods involved collection of blood at baseline, prior to alemtuzumab administration, and at months 5, 11, 17, 23, 36, and 48 post-treatment.

Activation of the Protective Arm of the Renin Angiotensin System in Demyelinating Disease.

The renin angiotensin system (RAS), which is classically known for blood pressure regulation, has functions beyond this. There are two axes of RAS that work to counterbalance each other and are active throughout the body, including the CNS. The pathological axis, consisting of angiotensin II (A1-8), angiotensin converting enzyme (ACE) and the angiotensin II type 1 receptor (AT1R), is upregulated in many CNS diseases, including multiple sclerosis (MS).

The influence of retinoic acid on the human oligodendrocyte precursor cells by RNA-sequencing.

Retinoic acid (RA), a metabolite of vitamin A, has been found to influence regeneration in the adult central nervous system (CNS). There may be an effect of RA in the recovery/repair in multiple sclerosis (MS), an autoimmune and neurodegenerative disease of the CNS. We hypothesized that RA is a regulator of the further differentiation of oligodendrocyte precursor cells (OPCs) - cells key to the remyelination process in MS.

In vitro assessment of the direct effect of laquinimod on basic functions of human neural stem cells and oligodendrocyte progenitor cells.

Laquinimod is an orally active immunomodulatory small molecule that has shown clear clinical benefit in trials for relapsing-remitting multiple sclerosis and in experimental rodent models that emulate multiple sclerosis (MS). Studies in healthy mice, and in mice with experimental autoimmune encephalomyelitis, have demonstrated that laquinimod is capable of entering the central nervous system. It is therefore important to determine if laquinimod is capable of a direct influence on basic functions of neural stem cells (NSC) or oligodendrocyte progenitor cells (OPC)--cells critical for myelin repair in MS.

Assessment of changes in immune measures of multiple sclerosis patients treated with laquinimod.

Laquinimod is a novel orally active agent with immunomodulatory properties that was shown to be effective in suppressing disease activity in relapsing-remitting multiple sclerosis patients. Though many mechanisms of action of laquinimod have been described, little is known about the in vivo effects of laquinimod on the functionality of circulating human peripheral blood mononuclear cell populations. We assessed both phenotypical and functional measures of PBMC in a prospective longitudinal analysis comparing laquinimod and placebo treated cohorts.

The dual role of CXCL8 in human CNS stem cell function: multipotent neural stem cell death and oligodendrocyte progenitor cell chemotaxis.

Research into multiple sclerosis (MS) has shown that cells purportedly important to myelin repair within the CNS, namely neural stem cells (NSC) and oligodendrocyte progenitor cells (OPC), are recruited to active lesion sites during the course of the disease. However, over time these cells appear to become depleted or functionally blocked in and around lesions, accompanied by a failure of repair mechanisms. We have previously demonstrated elevated CXCL8 in patients with MS, and hypothesized that this chemokine may play a role in the pathology of this disease.

The geometric and spatial constraints of the microenvironment induce oligodendrocyte differentiation.

The oligodendrocyte precursor cell (OPC) arises from the subventricular zone (SVZ) during early vertebrate development to migrate and proliferate along axon tracts before differentiating into the myelin-forming oligodendrocyte. We demonstrate that the spatial and temporal regulation of oligodendrocyte differentiation depends intimately on the axonal microenvironment and the density of precursor cells along a specified axonal area. Differentiation does not require dynamic axonal signaling, but instead is induced by packing constraints resulting from intercellular interactions.

Measuring apoptosis in neural stem cells.

In trauma to, and diseases of, the central nervous system (CNS), apoptotic events are frequently observed in and around areas of damage. Human embryonic stem cells (hESCs) and their progeny have been suggested as possible therapeutic agents in the treatment of CNS diseases. The success of stem cell transplantation not only depends on the capacity of these cells to retain their functionality after transplant into the CNS but also on their ability to resist the in situ environmental cues that may lead to apoptosis.

Characterisation of UBP296: a novel, potent and selective kainate receptor antagonist.

Willardiine derivatives with an N3-benzyl substituent bearing an acidic group have been synthesized with the aim of producing selective antagonists for GLUK5-containing kainate receptors. UBP296 was found to be a potent and selective antagonist of native GLUK5-containing kainate receptors in the spinal cord, with activity residing in the S enantiomer (UBP302). In cells expressing human kainate receptor subunits, UBP296 selectively depressed glutamate-induced calcium influx in cells containing GLUK5 in homomeric or heteromeric forms.

Pyruvate limits zinc-induced rat oligodendrocyte progenitor cell death.

A growing body of evidence suggests that excessive Zn2+ release plays a key role in inducing neuronal death during central nervous system injury. However, the possible cytotoxicity of extracellular Zn2+ to oligodendrocyte lineage cells remains unknown. Employing cultures of rat oligodendrocyte progenitor cells (OPC), we report here that OPC are vulnerable to increased extracellular Zn2+ levels and that pyruvate limits Zn2+-induced OPC death.

Characterisation of zinc uptake into rat cultured cerebrocortical oligodendrocyte progenitor cells.

In the mammalian brain, extracellular Zn(2+) is reported to play a neuromodulatory role and, during acute CNS injury, increased Zn(2+) release may be neurotoxic. Although several recent studies have examined possible mechanisms of neuronal Zn(2+) accumulation, little is known about oligodendroglial Zn(2+) uptake, the focus of the present study. 65Zn(2+) uptake was time-dependent and saturable (K(m)=3.